This invention relates to a new medical use for bupropion and physiologically acceptable salts and solvates thereof. Specifically the invention concerns the use of bupropion in treating viral infections, more particularly infections caused by viruses of the Herpes family.
Bupropion hydrochloride, (xc2x1)-1-(3-chlorophenyl)-2-[(1,1-di-methylethyl)-amino]-1-propanone hydrochloride has been used for the treatment of depression. Bupropion is a relatively weak inhibitor of the neuronal uptake of noradrenaline (NA), serotonin and dopamine (DA), and does not inhibit monoamine oxidase. While the mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Available evidence suggests that bupropion is a selective inhibitor of noradrenaline (NA) at doses that are predictive of antidepressant activity in animal models. See Ascher, J. A., et al., Bupropion: A Review of its Mechanism of Antidepressant Activity. Journal of Clinical Psychiatry, 56: p. 395-401,1995.
It has also been disclosed that bupropion is useful for the treatment of migraine (U.S. Pat. No. 5,753,712), reducing cholesterol (U.S. Pat. No. 4,438,138), treatment of minimal brain dysfunction (U.S. Pat. No. 4,435,449), treatment of tardive dyskinesia (U.S. Pat. No. 4,425,363), reversing impaired mental alertness due to ethanol consumption (U.S. Pat. No. 4,393,078), treatment of psychosexual dysfunction (U.S. Pat. No. 4,507,323), suppressing prolactin secretion (U.S. Pat. No. 4,347,257) and as an aid to smoking cessation.
The Herpes family of viruses is responsible for a wide range of infectious diseases in several species, including chicken pox, shingles, retinitis, pneumonitis and keratitis in humans and diseases of the skin and mucosa, including keratitis in rabbits, herpetic encephalitis in mice, Herpes viruses include Herpes zoster, HSV1 and HSV2 (Herpes Simplex Virus type 1 and type 2), hCMV and mCMV (human and murine cytomegalovirus), VZV (varicella zoster virus), EBV (Epstein barr virus) HHV6 and HHV8 (human herpes viruses, types 6 and 8).
There is a need in the art to develop novel therapies for the treatment and prevention of viral infections such as infections caused by the Herpes virus.
The present inventor has surprisingly demonstrated that bupropion is useful for the prevention and treatment of viral infections. In particular, the inventor has shown that bupropion is useful for the treatment and prevention of certain symptoms of viral infections caused by a herpes virus. More specifically, the inventor has shown bupropion is useful for the treatment of symptoms caused by a Herpes Simplex Virus. Bupropion is thus of potential benefit in the treatment of infections of viruses of the Herpes family or conditions caused thereby, particularly Herpes Simplex Virus (HSV) 1, HSV2, Herpes zoster and Varicella zoster. 
Accordingly, the present invention provides a use of bupropion for the manufacture of a medicament for the prevention or treatment of a viral infection. The present invention also provides a use of bupropion to prevent or treat a viral infection. The present invention further provides a method of treating and preventing a viral infection comprising administering an effective amount of bupropion to an animal in need thereof.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
As hereinbefore mentioned, the present inventor has demonstrated that bupropion is useful in the prevention or treatment of viral infections. The present inventor has shown that bupropion is superior to many other anti-viral agents such as acyclovir and famciclovir in the treatment and prevention of infections caused by the herpes virus.
Accordingly, the present invention provides a use of bupropion or a physiologically acceptable salt, solvate or enantiomer thereof for the manufacture of a medicament for the prevention or treatment of a viral infection. The present invention also provides a use of bupropion or a physiologically acceptable salt, solvate or enantiomer thereof to prevent or treat a viral infection. The present invention further provides a method of treating and preventing a viral infection comprising administering an effective amount of bupropion or a physiologically acceptable salt, solvate or enantiomer thereof to an animal in need thereof.
The term xe2x80x9ceffective amountxe2x80x9d as used herein is an amount effective, at dosages and for periods of time necessary to treat or prevent a viral infection.
The term xe2x80x9canimalxe2x80x9d as used herein includes all members of the animal kingdom including humans.
The term xe2x80x9cbupropionxe2x80x9d as used herein includes all physiologically acceptable salts and solvates thereof and all enantiomers thereof.
The bupropion for use in the invention is suitably in the form of a physiologically acceptable salt. This salt may include an acid addition salt formed with organic or inorganic acids for example hydrochloride, hydrobromide, sulphate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maleate and succinate. Preferably, the bupropion is in the form of its hydrochloride salt. The chemical structure of bupropion hydrochloride is shown below. 
Bupropion for use according to the invention may be administered as the raw chemical comprising the active compound. Preferably, the bupropion is formulated into a pharmaceutically acceptable composition or medicament. Conveniently, bupropion for use according to the invention may be formulated in conventional manner using one or more pharmaceutically acceptable excipients. Thus, bupropion for use according to the invention may for example be formulated for oral, sub-lingual, buccal, parenteral, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
For oral administration the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art.
Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl P-hydroxybenzoates or sorbic acid).
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
Bupropion for use according to the invention may be formulated for parenteral administration by injection, conveniently intravenous, in intramuscular or subcutaneous injection. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, optionally with an added preservative.
The compositions for parenteral administration may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in dry form such as a powder, crystalline or freeze-dried solid for constitution with a suitable vehicle, e.g. sterile pyrogen-free water or isotonic saline before use. They may be presented, for example, in sterile ampoules or vials.
Bupropion for use according to the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride. Tablets for sub-lingual administration may be formulated in a conventional manner.
For intranasal administration, bupropion for use according to the invention may be used, for example, as a liquid in the form of a spray or drops or as a powder. Suitably the preparation for intranasal administration is delivered in the form of a spray or aerosol from an insufflator or from a pressurised pack or nebuliser with the use of a suitable propellant.
For administration by inhalation, bupropion for use according to the invention is conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflater may be formulated containing a powder mix of a compound of use in the invention and a suitable powder base such as lactose or starch.
Various formulations of bupropion have been disclosed in U.S. Pat. Nos. 5,427,798, 5,358,970, 5,541,231, 5,731,000 and 5,763,493 (and other patents related to U.S. Pat. No. 5,358,970) all of which are incorporated herein by reference.
As indicated above, bupropion is of therapeutic and prophylactic benefit in the treatment of viral infections. In particular, bupropion is useful in the prevention and treatment of infectious diseases and conditions caused by viral infections. Such diseases include chicken pox (Varicella zoster), shingles (Herpes zoster), keratitis in rabbits, herpetic encephalitis in mice, cutaneous herpes in guinea pigs, cold sores (herpes labialis) and genital herpes (herpes simplex virus) in humans, retinitis, pneumonitis and keratitis in humans (hCMV), as well as diseases caused by Epstein Barr Virus (EBV), human herpes virus 6 (HHV 6), HHV 7 and HHV 8 and Human Immune deficiency Virus (HIV). Of particular mention are chicken pox, shingles, cold sores and genital herpes in humans; of special mention are cold sores and genital herpes in humans.
The terms xe2x80x9ctreatment and preventionxe2x80x9d include the prophylaxis, prevention of recurrence of symptoms and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions caused by a viral infection.
It will be appreciated that the precise dose of bupropion administered will in general depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician. The compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day, for one or two days.
Typically, bupropion is useful for the treatment and prevention of a viral infection in an amount between 0.1 mg to 1000 mg per day, more preferably in an amount between 25 mg and 600 mg per day and most preferably in an amount between 150 mg to 300 mg per day. Preferably, the bupropion is given for at least two days.
Typically, pharmaceutical compositions comprise bupropion in the amount of 0.1 mg to 500 mg per unit dose, more preferably in an amount between 25 mg and 300 mg per unit dose and most preferably in an amount between 50 mg to 150 mg per unit dose.
The total amount of bupropion taken to prevent or treat a viral infection or a particular episode of a recurrent viral infection is typically between about 50 mg and about 2000 mg, more preferably between about 150 mg and about 1500 mg, most preferably between about 300 mg and 1200 mg.
The bupropion may be administered in combination with other anti-viral agents that are useful in the treatment or prevention of a viral infection, such as infections caused by a herpes virus.